The mouth is a habitat for microbial growth and colonization. Within the mouth, the gums, lips, oral mucosa (cheek), palate, tongue and teeth provide surfaces for the colonization and accumulation of bacteria. Teeth are unique in the oral cavity because they have hard, non-shedding surfaces where bacteria and their products (dental plaque) can significantly accumulate, especially in approximal areas and along the gingival crevice.
Dental plaque is a rough sticky film on the teeth that is made up of saliva, bacteria and food particles which adheres tenaciously to teeth at points of irregularity or discontinuity. Within a few hours of teeth cleaning, a film of salivary mucus, consisting primarily of proteins, forms on the teeth. Various oral bacteria colonize the mucus and multiply, forming a layer of plaque. Carbohydrate food debris adheres to the mucus and is digested by some types of plaque-causing bacteria. The digestion produces both by-products which add to the plaque and acid which erodes tooth enamel.
The oral bacteria in dental plaque includes many gram positive and gram negative microorganisms embedded in an extracellular matrix of insoluble polysaccharides, firmly attached to teeth and other oral surfaces. The colonization of bacteria to form dental plaque follows an ecological pattern where a few pioneer aerobic species, mostly gram-positive streptococci, colonize enamel surfaces. The plaque then progresses through stages of increasing microbial complexity. Mature plaques, often found in protected regions of the teeth, such as cracks, approximal regions and in the gingival crevice, typically contain anaerobes. Saliva and crevicular fluid are a source of nutrients for the dental plaque. Local conditions affect the metabolic activity and composition of dental plaque.
To inhibit the growth of dental plaque, cationic antimicrobial agents have been used in some known oral compositions. However, their performance may be seriously compromised when used with anionic components, such as surfactants, fluoride and pyrophosphate, or the silica abrasives commonly found in dentifrices. Another antiplaque agent, the zinc cation, most often delivered as the relatively insoluble zinc citrate trihydrate salt, can be formulated into dentifrices but only provides a slight inhibitory effect on plaque formation.
Nonionic antibacterial agents have also been used in oral compositions. Such agents include phenols, such as thymol and eucalytol; halogenated salicylanilides; and halogenated hyroxydiphenyl ethers, such as triclosan.
Triclosan is a particularly attractive nonionic antibacterial because it is compatible with dentifrice components and has a broad antimicrobial spectrum with no sign that long-term use produces triclosan-resistant bacterial strains (Marsh, P.D., Dentifrices Containing New Agents for the Control of Plaque and Gingivitis: Microbiological Aspects. J. Clin. Periodontol. 18:462-67 (1991)). Triclosan has been shown to inhibit Gram-negative gingivitis pathogenic bacteria selectively, and to reduce the ratio of anaerobic to aerobic bacteria (Marsh, 1991 ). However, triclosan's major drawback is its limited water solubility (1 ppm in distilled water at 20.degree. C.). In light of this drawback, previous disclosures have focused on delivering triclosan to the oral cavity in an optimal fashion.
The efficacy of many antimicrobials is greatly influenced by their substantivity in the oral cavity. Each antibacterial has a concentration below which it exhibits little or no activity and less substantive antimicrobials have steeper decay curves. Generally, the longer the antimicrobial's concentration remains above that concentration needed for bacteriocidal activity, the more effective is the antimicrobial.
The substantivity of triclosan is complicated by its poor aqueous solubility. In previous disclosures, triclosan is emulsified by a surfactant in dentifrice to form lameliar, micellar or other surfactant phases. Upon dilution in the mouth, the concentration of surfactant, within a few minutes, falls below the critical micelle concentration (CHC) for a dentifrice surfactant (typically sodium dodecyl sulphate (CMC=0.23%)) and triclosan is precipitated. The precipitated triclosan would probably be biologically inactive and be removed from the oral cavity by ingestion or expectoration.
One disclosed method to improve delivery of triclosan to the oral cavity is to incorporate a lipophilic copolymer of methoxyethylene and maleic acid which enhances the delivery and retention of triclosan on teeth and oral soft tissues (U.S. Pat. No. 4,894,220, Nabi et al., issued Jan. 16, 1990) (c.f. Am. J. Dent. 3:S1-S72 (1990)). This reference discloses triclosan solubilized in the propylene glycol used as a humectant in the dentifrice formulation.
Another method of utilizing triclosan is in combination with zinc citrate trihydrate (Lane et al., Eur. Pat. Appl. No. 0,161,899 published Nov. 21, 1985). The combination of zinc citrate trihydrate and triclosan has been reported to have an additive effect on anti-plaque and anti-gingivitis activity. Eur. Pat. Appl. No. 0,161,899 discloses dentifrices in which zinc induces a lamellar surfactant phase with triclosan and the sodium dodecyl sulphate surfactant. This solubilizes the triclosan and helps deliver the antimicrobial to the plaque. It has been suggested that there is a correlation between the spacing of the lamellar surfactant phase in a zinc-triclosan dentifrice and its antiplaque effect (Van der Ouderaa, F. J. and Cummins, D., Delivery Systems for Agents in Supra- and Sub-gingival Plaque Control, J. Dent. Res, 68:1617-24. (1989)). However other published human studies have concluded that that there is little benefit from triclosan when used alone or in combination with zinc citrate (Addy, M., Jenkins, S., Newcombe, R., Toothpastes Containing 0.3% and 0.5% Triclosan (II): Effects of Single Brushings on Salivary Bacterial Counts, Am. J. Dent. 2:215-19 (1989); Jenkins, S., Addy, H., Newcombe, R., Toothpastes Containing 0.3% and 0.5% Triclosan (I): Effects on 4-day Plaque Regrowth, Am. J. Dent. 2:211-214 (1989); Addy, H, Jenkins, S., Newcombe, R., Studies on the Effect of Toothpaste Rinses on Plaque Regrowth (II): Triclosan With and Without Zinc Citrate Formulations, J. Clin. Periodontol. 16:385-387 (1989)).
Triclosan is known to be an antibacterial. (See, U.S. Pat. No. 3,629,477 issued Dec. 21, 1971 to Model & Bindlet.) Triclosan has been used in dentifrices. (C.f. Japanese Pat. No. Hei 2-1402, Katsuda et al. published Jan. 5, 1990; U.S. Pat. No. 4,980,153, Jackson et al., issued December 25, 1990; Eur. Pat. Appl. No. 0 161 899, Lane et al., assigned to Unilever, published Nov. 21, 1985; Eur. Pat. Appl. 0 278 744, Caserio et al., assigned to Unilever, published Aug. 17, 1988; Canadian Patent Application 0 961 412, Vinson & Cancro, issued Jan. 21, 1975).
Substituted triclosan compounds have been disclosed in United Kingdom Pat. No. 01 592 011, Reinhardt & Joachim, assigned to Ciba-Geigy AG, published Jul. 1, 1981. The reference teaches that substituted diphenyl ethers are excellent algicides if they contain a group which, on application of the compounds, is able to form the hydroxyl group; the reference discloses as one such compound 2,4,4'-trichloro-2'R-diphenyl ether where R=(HO).sub.2 PO--O--. The reference discloses the use of these compounds for the control of algae and the inhibition of algae growth.
Kamat, Biochemical Aspects of Periodontal Diseases: II. The Possible Significance of Calcium, Phosphorus, and Alkaline Phosphatase in Human Saliva, 50 J. Indian Dent. Assoc. 171-75 (1978) discloses that alkaline phosphatase in the oral cavity increases with increasing periodontosis severity. See Also, Miglani, et al., Salivary Phosphatases III: Possible Relation between Salivary Alkaline Phosphatase Activity and Gingival Inflammation, J. Periodontology, 45(7), 511-13 (1974).
Chemically modifying a drug to convert it into a prodrug is also known. See, Hiller, A Better Way to Hake the Medicine Go Down, 253 Science 1095-96 (Sep. 6, 1991).
It is an object of the subject invention to provide oral care compositions comprising certain antibacterial derivatives useful for treating or preventing plaque, gingivitis or periodontal diseases.
It is also an object of the subject invention to provide methods for treating or preventing plaque, gingivitis or periodontal disease.